Cardiac hypertrophy, associated with reduced myocardial contractility, develops in response to chronic pressure overloading of the heart. Overall heart function often deteriorates with chronic pressure overloading, resulting in the development of congestive heart failure. The biochemical factors which contribute to reduced contractility and the frequent deterioration in overall function observed in pressure-overload hypertrophied hearts are not fully understood. Changes in myocardial lipid metabolism have been associated with altered ventricular function under various pathological conditions. However, lipid metabolism has not been extensively studied in hearts subjected to chronic pressure overloading. The studies proposed in this application are directed toward determining the regulation of fatty acid oxidation and esterification to complex lipids in the pressure-overload hypertrophied heart. Preliminary work has shown that total tissue levels of coenzyme A (CoA) and carnitine, essential cofactors for fat metabolism, are markedly reduced in the hypertrophied myocardium. A major part of the proposed work is therefore designed to detemine if reductions in these cofactors are associated with alterations in fatty acid utilization by the heart. Cystolic and mitochondrial levels of CoA and carnitine and levels of fatty acyl intermediates will be determined in hearts of rats subjected to aortic constriction. Rates of fatty acid oxidation and fatty acid incorporation into triglycerides and phospholipids will be studied in hypertrophied hearts by employing the isolated perfused rat heart preparation. CoA synthesis and carnitine transport will also be examined in perfused hearts to determine the mechanisms involved with reduced tissue levels of these cofactors. Studies on lipid metabolism in the hypertrophied heart may facilitate a better understanding of the factors which contribute to reduced myocardial contractility in hypertrophied and failing hearts.